Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment

Primary tumors are drivers of pre-metastatic niche formation, but the coordination by the secondary organ toward metastatic dissemination is underappreciated. Here, by single-cell RNA sequencing and immunoflu-orescence, we identified a population of cyclooxygenase 2 (COX-2)-expressing adventitial fibroblasts that remodeled the lung immune microenvironment. At steady state, fibroblasts in the lungs produced prosta-glandin E2 (PGE2), which drove dysfunctional dendritic cells (DCs) and suppressive monocytes. This lung -intrinsic stromal program was propagated by tumor-associated inflammation, particularly the pro -inflamma-tory cytokine interleukin-1b, supporting a pre-metastatic niche. Genetic ablation of Ptgs2 (encoding COX-2) in fibroblasts was sufficient to reverse the immune-suppressive phenotypes of lung-resident myeloid cells, resulting in heightened immune activation and diminished lung metastasis in multiple breast cancer models. Moreover, the anti-metastatic activity of DC-based therapy and PD-1 blockade was improved by fibroblast -specific Ptgs2 deletion or dual inhibition of PGE2 receptors EP2 and EP4. Collectively, lung-resident fibro-blasts reshape the local immune landscape to facilitate breast cancer metastasis.

Automated summary

This study identified a population of fibroblasts that express COX-2 and remodel the lung immune microenvironment, promoting breast cancer metastasis. Genetic ablation of COX-2 in fibroblasts reversed the immune-suppressive phenotypes and improved the anti-metastatic activity of DC-based therapy and PD-1 blockade.